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Check out this article:http://www.biotechmedia.com/mar_pro_citation_art05-00.html

IntroductionFor most lay people, the closest they’ve come to a drug-labeling dilemma is a Hollywood film classic. I’m referring to Frank Capra’s 1940’s Christmas movie; It’s a Wonderful Life. In the first reel the director introduces us to a young Jimmy Stewart, who’s working after school in the local pharmacy. Tragically, the pharmacist has just been notified that his only son has been killed in the war.

Bereaved, overwrought, and somewhat tipsy, the pharmacist incorrectly fills an urgent prescription. Young Stewart witnesses the error and returns to the pharmacy without delivering the deadly mistake: for which he suffers a literal boxing to the ears by the irate pharmacist, until he realizes the boy is not a laggard but a hero. The boy’s hearing is permanently damaged, but a terrible tragedy was avoided.

Everyone in the worldwide clinical labeling industry is familiar with that scene, and we cringe every time we see it. In the business of clinical labeling, one hundred percent compliance is not a goal to be strategized over and eventually achieved. It is the day to day, 24/7, SOP of this industry. The alternative is not and never will be an option.

This paper will outline the history, physical properties, regulatory environment, and future of our unique industry.

Clinical Labeling: A History of Growth via TechnologyOver the past fifty years we’ve seen tremendous change in our industry. From typewriters and rubber bands to semi-automatic filling to fully-automated print and fill to digitally verified multi-lingual labels and Web-based ordering: the labeling of new drugs has benefited from growth via several key technological breakthroughs.

Many of the labeling industry’s leading companies were born of successful post-World War II printing shops. Two events shaped the industry into its modern form. Chemical discoveries that yielded new adhesives and secondly, the graphics and communications capabilities of the computer.

Until the advent of the modern adhesives industry almost all labeling was affixed to the container via rubber bands or string. The industrial revolution and most significantly, World War II saw the refinement of polymer adhesives that would revolutionize the industry. New polymer adhesives were now affordable, and drug labeling was as they say, a Killer App.

Postwar demand for everything was intense, and everything needed a label. Labeling for medicinals became a specialty. The requirements for success in this new business were unique. The need for 100% accuracy was, as always, the standard. These post war entrepreneurs knew the importance of accuracy and timeliness. They also understood the consequence and liability for careless errors, and had the confidence to meet it head-on with diligence, hard work, and ingenuity.

The last decade of the 20th century brought significant changes in the automation of the clinical trial labeling process. Most significant is the Squibb story.

Beginning in 1987, Squibb’s Pharmaceutical Research Institute in New Brunswick, NJ, sought to revolutionize the industry with a fully automated labeling and fill process. They correctly forecasted the dramatic growth in new clinical trial drugs, put their operation under a microscope, and discovered an opportunity for a tenfold increase in productivity. While always maintaining their goal of absolute product accuracy, Squibb began by acquiring automatic filling and capping equipment for their clinical packaging group. The groups clinical programs were growing in number of patients and new therapies.

After years of experimenting with several three-panel labels, they chose a vendor that produced a patterned-coated label. In this new configuration the first panel received a permanent adhesive while the second and third panels received a temporary adhesive. The first panel, which was permanently affixed, contained the patient directions and the coded patient number. The second panel contained the same information as the first but was separated, attached to the case report form (CRF) and put into the patients case report file. The third panel was sent to the sponsor/investigator. It contained the identity of the drug, which was hidden from the doctor and patient, and thus the term “double blind.” Squibb and their various vendors successfully and accurately met a challenge and advanced an industry to its next level.

Unfortunately and ironically, today’s clinical trial drugs often require multiple label panels on one container, especially for clinical trials that require multi-lingual panels. As a result of the quantity of information required, we have to guard against a reversion back to the rubber band and string era. This challenge is being met as usual, via technology and the Expanded-Content Label (ECL).

The advancements in technology, such as thermal and laser printing, combined with the accuracy of computer generated medical and drug data, have allowed everyone connected with the dispensing of clinical trial drugs to breathe a little easier.

U.S. Regulations Governing Clinical Trial LabelingThere is one absolute when dealing with the FDA or any overseas regulatory authority and it’s grounded in common sense: every drug must be correctly labeled and when possible, permanently affixed to the container. Obeying this simple rule doesn’t appear at first to be much of a burden on sponsors and investigators. However, add to this equation the following: more and more FDA mandated information must appear on the label, the growth of multi-drug trials, and multi-lingual trials, and you have a potential labeling nightmare. Several international trade associations, working with the International Commission on Harmonization (ICH) as well as those in private industry continue to work to find the best solutions.

As of this writing and at the end of April, the U.S. Government will release the 2000 edition of the Code of Federal Regulations. The CFR provides the public with the day to day regulations of various Federal Government agencies. Title 21 of the CFR is entitled Food and Drugs and contains the forms and procedures to be followed by persons or corporations in the food and drug business. Suffice it to say that while every April brings springtime and Apple Blossoms to Washington DC, it also brings more and more regulations that must be read, studied and interpreted by the rest of the world. There is hope though.

Thanks to the achievements of the International Commission on Harmonization (ICH), the Food and Drug Administration (FDA), and its’ counterpart in Europe, the European Agency for the Evaluation of Medicinal Products, our industry is moving closer to the goal of unified and simplified clinical trial procedures. The CFR, mentioned earlier, specifically addresses the ICH’s efforts as follows:

Sec. 26.48 Harmonization.During both the transitional and operational phases of this subpart, both parties intend to continue to participate in the activities of the Global Harmonization Task Force (GHTF) and utilize the results of those activities to the extent possible. Such participation involves developing and reviewing documents developed by the GHTF and jointly determining whether they are applicable to the implementation of this subpart.

Citations of several of the more important U.S. labeling regulations are listed at the end of this article.

Physical Properties of the Modern Clinical Trial LabelThe Squibb experience of using two types of adhesives on one label, permanent and removable,was only one of the new advances this venture produced. It also resulted in changing the very structure of the label.

Through the use of special chemicals within the label itself, they raised the bar regarding clinical trial confidentiality. This is how it worked: the third panel of Squibb’s three-panel label contained the name of the drug under investigation. This information was hidden within a pocket built inside the overprinted label stock. The back of the pocket had an on-press application (OPAS) chemical coating. When pressure was applied to the top of the pocket, the coated-back sheet and chemical coating interact to produce a readable image. After testing and more testing the system worked and the clinical trial labeling business took a giant step forward.

As mentioned, adhesion is one of the most important physical properties of any clinical trial label. Many of the human and financial risks associated with mislabeling an investigational new drug can be ameliorated as long as the package contents are correctly manifested on the label. If Jimmy Stewart’s character were in a modern-day clinical trial setting, he might also want to tell the grumpy pharmacist, “ ...you also almost cost ABC BigPharma Corporation, a $100 million investment!”

Unlike most product labeling, clinical trial labels must occasionally perform under extreme environmental conditions. Usage and storage conditions are critical when making a labeling decision. Certain adhesives work better in refrigerated conditions. Storage conditions of labeled drugs must be sensitive to temperature, humidity, and the external environment. In addition, the safety and security protocol procedures must withstand a variety of these usage conditions.

Labels must also conform to the container designated to carry the drug under study. Some choices available at this writing are high and low density polyethylene bottles, glass bottles, metal (usually aluminum), polyethylene or tyvek bags, coated or uncoated SBS board, and corrugated board.

As always during any clinical trial, sponsors and investigators are responsible for choosing the proper container and verifying that it meets the labeling and storage protocol and the label supplier’s capabilities. Label face materials once meant a black or red typewriter ribbon. Sponsors now have a choice of:EDP, litho (plain or opaque), laser (plain or premium), thermal (plain or opaque), Kimdura (plain or opaque), plus a variety of other synthetic materials. The longevity of the printed information must also take into consideration extreme environmental conditions.

The choice of the best label adhesive has been expanded to include permanent, removable, patterned, multiple, and refrigerated-extreme environments.

As the cost of bringing a new drug to market increases, so does the importance of maintaining label protocol with the blinding method chosen. The inherent risks of dealing with real people with real diseases, demand that the labeling decision protect confidentiality. The labeling choices include glued pocket, scratch-off laminate and disclosure envelopes.

Like any industry, the clinical labeling industry has their share of buzzwords, likeScratchGuard ™, Expanded-Content Label, (ECL), Multi-Lingual, Tamper-Proof, etc. These speak to the direction all successful industries take: keep identifying customer needs and discover better ways to satisfy them.

Beyond Y2K for the Clinical Labeling IndustryIntra-industry stories like Squibb have more recently been replaced by several negative exposés on the clinical trial process itself. As a result of some unfortunate trial outcomes, the general media’s interest in the clinical trial process has been piqued. And not surprisingly, the general media overlooks the facts in favor of the sensational, which is usually an unhappy trial participant.

There are some exciting developments in Clinical Trial Management that should reassure the general public and bring the process itself out of the 20th century. Electronic Data Collection promises to provide the level of data security and impartiality that all trial participants deserve. EDC involves the collection of real-time patient data using Electronic CRFs and distribution of information using secure Internet links.

Also on the positive side, Wall Street’s interest (though fickle at times) in biotech and in the drug discovery business, has provided our industry with a healthy dose of good PR.

We expect the future will bring more regulations both here and overseas as we see more and more clinical trials following the international route to patient enrollment.

The financial stakes are growing daily, the human genome has just been completely deciphered, and the labeling industry will respond as they have for years with new products, new services, and new solutions to meet the requirements of the world’s biotech and pharmaceutical industry.

Other Resources:

The US Government has provided all of us with a unique resource, the Government Printing Office. Fortunately you needn’t fly or drive to DC and search through the nation's congressional archives. The GPO also has the responsibility for making available to the public all relevant regulations via the Internet. The citations listed below can be accessed from the following Web site: www.gpo.gov. Follow the links to the Code of Federal Regulations-Search Page, and enter in the search box the following:

The following references are a portion of the results of the search mentioned above:

TITLE 21--FOOD AND DRUGS, PART 201—LABELING, Subpart A--General Labeling ProvisionsSubpart B--Labeling Requirements for Prescription Drugs and/or Insulin 201.58 Requests for waiver of requirement for adequate and well-controlled studies to substantiate certain labeling statements.Subpart D--Exemptions From Adequate Directions for Use 201.125 Drugs for use in teaching, law enforcement, research, and analysis.Subpart F--Labeling Claims for Drugs in Drug Efficacy Study 201.200 Disclosure of drug efficacy study evaluations in labeling and advertising.TITLE 21--FOOD AND DRUGS, PART 312--INVESTIGATIONAL NEW DRUG APPLICATION 312.3 Definitions and interpretations. 312.6 Labeling of an investigational new drug.Subpart D--Responsibilities of Sponsors and Investigators 312.57 Recordkeeping and record retention. 312.88 Safeguards for patient safety. 312.120 Foreign clinical studies not conducted under an IND.

2. Code of Federal Regulations, April 1999 Title 21 Part 201, Subpart A

3. Code of Federal Regulations, April 1999 Title 21, Sec 26.48

4. Code of Federal Regulations, April 1999 Title 21 Part 312, Subpart D

About the Author

Mr. Richard Bolnick is the President of Citation Clinical Labeling Systems of Farmingdale, New York. A 1987 graduate of The University of Pennsylvania, Mr. Bolnick majored in Sociology and Entrepreneurial Management and received a Bachelor of Arts degree. Since joining Citation in 1987, Mr. Bolnick has been co-awarded two patents in the clinical labeling field. In 1997 Mr. Bolnick became President of Citation.(Click here for their latest ad campaign)